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Biology and Sex Disparities in Melanoma Outcomes

  • Adi Nosrati
  • Maria L. Wei
Chapter

Abstract

The incidence of malignant melanoma in most developed countries has risen faster than any other cancer type; In the United States in 2016, women accounted for 39% of the 76,380 new cases of invasive cutaneous melanoma, and only 33% of the 10,130 were melanoma-related deaths. Gender differences in melanoma incidence and outcomes have been consistently observed even when adjusting for prognostic factors such as age, Breslow thickness, body site, ulceration, lymph node dissection, and for treatment. The mechanisms underlying this disparity are not well understood but likely related to both behavioral and biological etiologies. This chapter examines the cumulative evidence for biologically based processes that lead to differences in melanoma biology in men and women, including inherent sex-based differences in immune function, oxidative stress response and vitamin D metabolism; the complex interplay between sex hormones, the immune system and oxidative stress response; the effect of non-random X chromosome inactivation on tumorigenesis; and the potential contribution of recently identified oncogenes on the Y chromosome.

Keywords

Melanoma Melanoma outcomes Gender disparities Sexual dimorphism Skin cancer 

Abbreviations

8-OG

8-Oxo-deoxyguanosine

AR

Androgen receptor

DSS

Disease-specific survival

E2

17-βeta-estradiol

ERα

Estrogen receptor alpha

ERβ

Estrogen receptor beta

HCC

Hepatocellular cancer

NAC

N-acetylcysteine

ROS

Reactive oxygen species

PD-1

Programmed cell death protein-1

Xm

Maternal X chromosome

Xp

Paternal X chromosome

Notes

Acknowledgments

Many thanks to Jerelyn Magnusson for technical assistance.

References

  1. 1.
    Erdei E, Torres SM. A new understanding in the epidemiology of melanoma. Expert Rev Anticancer Ther. 2010;10(11):1811–23.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    MacKie RM, Hauschild A, Eggermont AM. Epidemiology of invasive cutaneous melanoma. Ann Oncol. 2009;20(Suppl 6):vi1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Lasithiotakis KG, Leiter U, Gorkievicz R, Eigentler T, Breuninger H, Metzler G, et al. The incidence and mortality of cutaneous melanoma in southern Germany: trends by anatomic site and pathologic characteristics, 1976 to 2003. Cancer. 2006;107(6):1331–9.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Coit DG, Andtbacka R, Anker CJ, Bichakjian CK, Carson WE 3rd, Daud A, et al. Melanoma, version 2.2013: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw. 2013;11(4):395–407.CrossRefGoogle Scholar
  6. 6.
    Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199–206.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Homsi J, Kashani-Sabet M, Messina JL, Daud A. Cutaneous melanoma: prognostic factors. Cancer Control. 2005;12(4):223–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Scoggins CR, Ross MI, Reintgen DS, Noyes RD, Goydos JS, Beitsch PD, et al. Gender-related differences in outcome for melanoma patients. Ann Surg. 2006;243(5):693–8; discussion 8-700.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Lasithiotakis K, Leiter U, Meier F, Eigentler T, Metzler G, Moehrle M, et al. Age and gender are significant independent predictors of survival in primary cutaneous melanoma. Cancer. 2008;112(8):1795–804.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Joosse A, Collette S, Suciu S, Nijsten T, Lejeune F, Kleeberg UR, et al. Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials. J Clin Oncol. 2012;30(18):2240–7.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Joosse A, de Vries E, Eckel R, Nijsten T, Eggermont AM, Holzel D, et al. Gender differences in melanoma survival: female patients have a decreased risk of metastasis. J Invest Dermatol. 2011;131(3):719–26.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    de Vries E, Nijsten TE, Visser O, Bastiaannet E, van Hattem S, Janssen-Heijnen ML, et al. Superior survival of females among 10,538 Dutch melanoma patients is independent of Breslow thickness, histologic type and tumor site. Ann Oncol. 2008;19(3):583–9.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Sondak VK, Swetter SM, Berwick MA. Gender disparities in patients with melanoma: breaking the glass ceiling. J Clin Oncol. 2012;30(18):2177–8.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Gamba CS, Clarke CA, Keegan TH, Tao L, Swetter SM. Melanoma survival disadvantage in young, non-Hispanic white males compared with females. JAMA Dermatol. 2013;149(8):912–20.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    American Cancer Society. Cancer facts and figures 2016. 2016. http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf. 6 June 2016.Google Scholar
  16. 16.
    Joosse A, Collette S, Suciu S, Nijsten T, Patel PM, Keilholz U, et al. Sex is an independent prognostic indicator for survival and relapse/progression-free survival in metastasized stage III to IV melanoma: a pooled analysis of five European Organisation for Research and Treatment of Cancer randomized controlled trials. J Clin Oncol. 2013;31(18):2337–46.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Gupta S, Artomov M, Goggins W, Daly M, Tsao H. Gender disparity and mutation burden in metastatic melanoma. J Natl Cancer Inst. 2015;107(11):djv221.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Micheli A, Ciampichini R, Oberaigner W, Ciccolallo L, de Vries E, Izarzugaza I, et al. The advantage of women in cancer survival: an analysis of EUROCARE-4 data. Eur J Cancer. 2009;45(6):1017–27.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Micheli A, Mariotto A, Giorgi Rossi A, Gatta G, Muti P. The prognostic role of gender in survival of adult cancer patients. EUROCARE Working Group. Eur J Cancer. 1998;34(14 Spec No):2271–8.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Fisher DE, Geller AC. Disproportionate burden of melanoma mortality in young U.S. men: the possible role of biology and behavior. JAMA Dermatol. 2013;149(8):903–4.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Kanda N, Watanabe S. 17beta-estradiol, progesterone, and dihydrotestosterone suppress the growth of human melanoma by inhibiting interleukin-8 production. J Invest Dermatol. 2001;117(2):274–83.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest. 2002;109(12):1625–33.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Merino R, Ding L, Veis DJ, Korsmeyer SJ, Nunez G. Developmental regulation of the Bcl-2 protein and susceptibility to cell death in B lymphocytes. EMBO J. 1994;13(3):683–91.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Sato S, Tuscano JM, Inaoki M, Tedder TF. CD22 negatively and positively regulates signal transduction through the B lymphocyte antigen receptor. Semin Immunol. 1998;10(4):287–97.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Cyster JG, Goodnow CC. Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection. Immunity. 1995;2(1):13–24.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Bynoe MS, Grimaldi CM, Diamond B. Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. Proc Natl Acad Sci U S A. 2000;97(6):2703–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Ruiz-Larrea MB, Leal AM, Martin C, Martinez R, Lacort M. Antioxidant action of estrogens in rat hepatocytes. Rev Esp Fisiol. 1997;53(2):225–9.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Borrás C, Sastre J, Garcia-Sala D, Lloret A, Pallardo FV, Vina J. Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med. 2003;34(5):546–52.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Allil PA, Visconti MA, Castrucci AM, Isoldi MC. Photoperiod and testosterone modulate growth and melanogenesis of s91 murine melanoma. Med Chem. 2008;4(2):100–5.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    McMurray RW, Suwannaroj S, Ndebele K, Jenkins JK. Differential effects of sex steroids on T and B cells: modulation of cell cycle phase distribution, apoptosis and bcl-2 protein levels. Pathobiology. 2001;69(1):44–58.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Sthoeger ZM, Chiorazzi N, Lahita RG. Regulation of the immune response by sex hormones. I. In vitro effects of estradiol and testosterone on pokeweed mitogen-induced human B cell differentiation. J Immunol. 1988;141(1):91–8.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Bokov AF, Ko D, Richardson A. The effect of gonadectomy and estradiol on sensitivity to oxidative stress. Endocr Res. 2009;34(1-2):43–58.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Barsony J, Pike JW, DeLuca HF, Marx SJ. Immunocytology with microwave-fixed fibroblasts shows 1 alpha,25-dihydroxyvitamin D3-dependent rapid and estrogen-dependent slow reorganization of vitamin D receptors. J Cell Biol. 1990;111(6 Pt 1):2385–95.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Liel Y, Kraus S, Levy J, Shany S. Evidence that estrogens modulate activity and increase the number of 1,25-dihydroxyvitamin D receptors in osteoblast-like cells (ROS 17/2.8). Endocrinology. 1992;130(5):2597–601.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Schwartz B, Smirnoff P, Shany S, Liel Y. Estrogen controls expression and bioresponse of 1,25-dihydroxyvitamin D receptors in the rat colon. Mol Cell Biochem. 2000;203(1-2):87–93.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Bouman A, Schipper M, Heineman MJ, Faas MM. Gender difference in the non-specific and specific immune response in humans. Am J Reprod Immunol. 2004;52(1):19–26.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Pinto RE, Bartley W. The effect of age and sex on glutathione reductase and glutathione peroxidase activities and on aerobic glutathione oxidation in rat liver homogenates. Biochem J. 1969;112(1):109–15.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Joosse A, De Vries E, van Eijck CH, Eggermont AM, Nijsten T, Coebergh JW. Reactive oxygen species and melanoma: an explanation for gender differences in survival? Pigment Cell Melanoma Res. 2010;23(3):352–64.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Vina J, Borras C, Gambini J, Sastre J, Pallardo FV. Why females live longer than males? Importance of the upregulation of longevity-associated genes by oestrogenic compounds. FEBS Lett. 2005;579(12):2541–5.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8(9):737–44.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Spolarics Z. The X-files of inflammation: cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection. Shock. 2007;27(6):597–604.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Renault NK, Pritchett SM, Howell RE, Greer WL, Sapienza C, Orstavik KH, et al. Human X-chromosome inactivation pattern distributions fit a model of genetically influenced choice better than models of completely random choice. Eur J Hum Genet. 2013;21(12):1396–402.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Segura MF, Belitskaya-Levy I, Rose AE, Zakrzewski J, Gaziel A, Hanniford D, et al. Melanoma microRNA signature predicts post-recurrence survival. Clin Cancer Res. 2010;16(5):1577–86.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Streicher KL, Zhu W, Lehmann KP, Georgantas RW, Morehouse CA, Brohawn P, et al. A novel oncogenic role for the miRNA-506-514 cluster in initiating melanocyte transformation and promoting melanoma growth. Oncogene. 2012;31(12):1558–70.CrossRefPubMedGoogle Scholar
  45. 45.
    Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 2005;5(8):615–25.CrossRefPubMedGoogle Scholar
  46. 46.
    Scanlan MJ. The cancer/testis genes: review, standardization, and commentary. Cancer Immun. 2004;4:1.PubMedGoogle Scholar
  47. 47.
    Caballero OL, Cohen T, Gurung S, Chua R, Lee P, Chen YT, et al. Effects of CT-Xp gene knock down in melanoma cell lines. Oncotarget. 2013;4(4):531–41.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Oram SW, Liu XX, Lee TL, Chan WY, Lau YF. TSPY potentiates cell proliferation and tumorigenesis by promoting cell cycle progression in HeLa and NIH3T3 cells. BMC Cancer. 2006;6:154.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Zhang JS, Yang-Feng TL, Muller U, Mohandas TK, de Jong PJ, Lau YF. Molecular isolation and characterization of an expressed gene from the human Y chromosome. Hum Mol Genet. 1992;1(9):717–26.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Lau YF, Li Y, Kido T. Role of the Y-located putative gonadoblastoma gene in human spermatogenesis. Syst Biol Reprod Med. 2011;57(1-2):27–34.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Li Y, Lau YF. TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities. Oncogene. 2008;27(47):6141–50.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Gallagher WM, Bergin OE, Rafferty M, Kelly ZD, Nolan IM, Fox EJ, et al. Multiple markers for melanoma progression regulated by DNA methylation: insights from transcriptomic studies. Carcinogenesis. 2005;26(11):1856–67.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Kemeny MM, Busch E, Stewart AK, Menck HR. Superior survival of young women with malignant melanoma. Am J Surg. 1998;175(6):437–44; discussion 44-5.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Koomen ER, Joosse A, Herings RM, Casparie MK, Guchelaar HJ, Nijsten T. Estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based case-control study. Ann Oncol. 2009;20(2):358–64.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    MacKie RM, Bray CA. Hormone replacement therapy after surgery for stage 1 or 2 cutaneous melanoma. Br J Cancer. 2004;90(4):770–2.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Naldi L, Altieri A, Imberti GL, Giordano L, Gallus S, La Vecchia C. Cutaneous malignant melanoma in women. Phenotypic characteristics, sun exposure, and hormonal factors: a case-control study from Italy. Ann Epidemiol. 2005;15(7):545–50.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Karagas MR, Stukel TA, Dykes J, Miglionico J, Greene MA, Carey M, et al. A pooled analysis of 10 case-control studies of melanoma and oral contraceptive use. Br J Cancer. 2002;86(7):1085–92.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Grin CM, Driscoll MS, Grant-Kels JM. The relationship of pregnancy, hormones, and melanoma. Semin Cutan Med Surg. 1998;17(3):167–71.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Gefeller O, Hassan K, Wille L. Cutaneous malignant melanoma in women and the role of oral contraceptives. Br J Dermatol. 1998;138(1):122–4.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Lambe M, Thorn M, Sparen P, Bergstrom R, Adami HO. Malignant melanoma: reduced risk associated with early childbearing and multiparity. Melanoma Res. 1996;6(2):147–53.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Lens M, Bataille V. Melanoma in relation to reproductive and hormonal factors in women: current review on controversial issues. Cancer Causes Control. 2008;19(5):437–42.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kvale G, Heuch I, Nilssen S. Parity in relation to mortality and cancer incidence: a prospective study of Norwegian women. Int J Epidemiol. 1994;23(4):691–9.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Smith MA, Fine JA, Barnhill RL, Berwick M. Hormonal and reproductive influences and risk of melanoma in women. Int J Epidemiol. 1998;27(5):751–7.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Sutherland CM, Loutfi A, Mather FJ, Carter RD, Krementz ET. Effect of pregnancy upon malignant melanoma. Surg Gynecol Obstet. 1983;157(5):443–6.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Trapeznikov NN, Khasanov ShR, Iavorskii VV. [Melanoma of the skin and pregnancy]. Vopr Onkol. 1987;33(6):40–6.Google Scholar
  66. 66.
    Pack GT, Scharnagel IM. The prognosis for malignant melanoma in the pregnant woman. Cancer. 1951;4(2):324–34.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Lens MB, Rosdahl I, Ahlbom A, Farahmand BY, Synnerstad I, Boeryd B, et al. Effect of pregnancy on survival in women with cutaneous malignant melanoma. J Clin Oncol. 2004;22(21):4369–75.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    O’Meara AT, Cress R, Xing G, Danielsen B, Smith LH. Malignant melanoma in pregnancy. A population-based evaluation. Cancer. 2005;103(6):1217–26.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P, et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 1986;320(6058):134–9.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    de Giorgi V, Mavilia C, Massi D, Gozzini A, Aragona P, Tanini A, et al. Estrogen receptor expression in cutaneous melanoma: a real-time reverse transcriptase-polymerase chain reaction and immunohistochemical study. Arch Dermatol. 2009;145(1):30–6.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Schmidt AN, Nanney LB, Boyd AS, King LE Jr, Ellis DL. Oestrogen receptor-beta expression in melanocytic lesions. Exp Dermatol. 2006;15(12):971–80.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Richardson B, Price A, Wagner M, Williams V, Lorigan P, Browne S, et al. Investigation of female survival benefit in metastatic melanoma. Br J Cancer. 1999;80(12):2025–33.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Roy S, Reddy BS, Sudhakar G, Kumar JM, Banerjee R. 17beta-estradiol-linked nitro-L-arginine as simultaneous inducer of apoptosis in melanoma and tumor-angiogenic vascular endothelial cells. Mol Pharm. 2011;8(2):350–9.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Dobos J, Timar J, Bocsi J, Burian Z, Nagy K, Barna G, et al. In vitro and in vivo antitumor effect of 2-methoxyestradiol on human melanoma. Int J Cancer. 2004;112(5):771–6.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Ghosh R, Ott AM, Seetharam D, Slaga TJ, Kumar AP. Cell cycle block and apoptosis induction in a human melanoma cell line following treatment with 2-methoxyoestradiol: therapeutic implications? Melanoma Res. 2003;13(2):119–27.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP, et al. The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature. 1994;368(6468):237–9.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Cho JL, Allanson M, Reeve VE. Oestrogen receptor-beta signalling protects against transplanted skin tumour growth in the mouse. Photochem Photobiol Sci. 2010;9(4):608–14.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Chang C, Lee SO, Yeh S, Chang TM. Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver. Oncogene. 2014;33:3225.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Rampen FH, Mulder JH. Malignant melanoma: an androgen-dependent tumour? Lancet. 1980;1(8168 Pt 1):562–4.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Brinton LA, Moghissi KS, Westhoff CL, Lamb EJ, Scoccia B. Cancer risk among infertile women with androgen excess or menstrual disorders (including polycystic ovary syndrome). Fertil Steril. 2010;94(5):1787–92.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Morvillo V, Luthy IA, Bravo AI, Capurro MI, Donaldson M, Quintans C, et al. Atypical androgen receptor in the human melanoma cell line IIB-MEL-J. Pigment Cell Res. 1995;8(3):135–41.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Hsueh EC, Gupta RK, Lefor A, Reyzin G, Ye W, Morton DL. Androgen blockade enhances response to melanoma vaccine. J Surg Res. 2003;110(2):393–8.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Brewer JD, Shanafelt TD, Otley CC, Roenigk RK, Cerhan JR, Kay NE, et al. Chronic lymphocytic leukemia is associated with decreased survival of patients with malignant melanoma and Merkel cell carcinoma in a SEER population-based study. J Clin Oncol. 2012;30(8):843–9.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Brewer JD, Christenson LJ, Weaver AL, Dapprich DC, Weenig RH, Lim KK, et al. Malignant melanoma in solid transplant recipients: collection of database cases and comparison with surveillance, epidemiology, and end results data for outcome analysis. Arch Dermatol. 2011;147(7):790–6.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Matin RN, Mesher D, Proby CM, McGregor JM, Bouwes Bavinck JN, del Marmol V, et al. Melanoma in organ transplant recipients: clinicopathological features and outcome in 100 cases. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2008;8(9):1891–900.CrossRefGoogle Scholar
  86. 86.
    Bouman A, Heineman MJ, Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update. 2005;11(4):411–23.CrossRefPubMedGoogle Scholar
  87. 87.
    Giltay EJ, Fonk JC, von Blomberg BM, Drexhage HA, Schalkwijk C, Gooren LJ. In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans. J Clin Endocrinol Metab. 2000;85(4):1648–57.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    McDonnell DP, Norris JD. Connections and regulation of the human estrogen receptor. Science. 2002;296(5573):1642–4.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Kanda N, Tamaki K. Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol. 1999;103(2 Pt 1):282–8.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Verthelyi D. Sex hormones as immunomodulators in health and disease. Int Immunopharmacol. 2001;1(6):983–93.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Verthelyi D, Ansar AS. Characterization of estrogen-induced autoantibodies to cardiolipin in non-autoimmune mice. J Autoimmun. 1997;10(2):115–25.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Mirandola L, Wade R, Verma R, Pena C, Hosiriluck N, Figueroa JA, et al. Sex-driven differences in immunological responses: challenges and opportunities for the immunotherapies of the third millennium. Int Rev Immunol. 2015;34(2):134–42.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Kanda N, Tsuchida T, Tamaki K. Testosterone inhibits immunoglobulin production by human peripheral blood mononuclear cells. Clin Exp Immunol. 1996;106(2):410–5.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Duffy DL, Bentley GE, Drazen DL, Ball GF. Effects of testerone on cell-mediated and humoral immunity in non-breeding adult European starlings. Behav Ecol. 2000;11(6):654–62.CrossRefGoogle Scholar
  95. 95.
    Hamid O, Carvajal RD. Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy. Expert Opin Biol Ther. 2013;13(6):847–61.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315(15):1600–9.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116(7):1757–66.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res. 2006;84(2):370–8.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol. 2007;19(3):337–43.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Lin PY, Sun L, Thibodeaux SR, Ludwig SM, Vadlamudi RK, Hurez VJ, et al. B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses. J Immunol. 2010;185(5):2747–53.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Nosrati A, Tsai KK, Goldinger SM, Tumeh P, Grimes B, Loo K, et al. Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy. Br J Cancer. 2017;116:1141.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Dronca RS, Dong H. A gender factor in shaping T-cell immunity to melanoma. Front Oncol. 2015;5:8.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Malorni W, Campesi I, Straface E, Vella S, Franconi F. Redox features of the cell: a gender perspective. Antioxid Redox Signal. 2007;9(11):1779–801.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Cotter MA, Thomas J, Cassidy P, Robinette K, Jenkins N, Florell SR, et al. N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of ultraviolet-induced melanoma in mice. Clin Cancer Res. 2007;13(19):5952–8.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Sander CS, Hamm F, Elsner P, Thiele JJ. Oxidative stress in malignant melanoma and non-melanoma skin cancer. Br J Dermatol. 2003;148(5):913–22.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Meyskens FL Jr, McNulty SE, Buckmeier JA, Tohidian NB, Spillane TJ, Kahlon RS, et al. Aberrant redox regulation in human metastatic melanoma cells compared to normal melanocytes. Free Radic Biol Med. 2001;31(6):799–808.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Nishikawa M. Reactive oxygen species in tumor metastasis. Cancer Lett. 2008;266(1):53–9.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Trouba KJ, Hamadeh HK, Amin RP, Germolec DR. Oxidative stress and its role in skin disease. Antioxid Redox Signal. 2002;4(4):665–73.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Thomas-Ahner JM, Wulff BC, Tober KL, Kusewitt DF, Riggenbach JA, Oberyszyn TM. Gender differences in UVB-induced skin carcinogenesis, inflammation, and DNA damage. Cancer Res. 2007;67(7):3468–74.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Malorni W, Straface E, Matarrese P, Ascione B, Coinu R, Canu S, et al. Redox state and gender differences in vascular smooth muscle cells. FEBS Lett. 2008;582(5):635–42.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Borras C, Gambini J, Lopez-Grueso R, Pallardo FV, Vina J. Direct antioxidant and protective effect of estradiol on isolated mitochondria. Biochim Biophys Acta. 2010;1802(1):205–11.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Berwick M, Erdei EO. Vitamin D and melanoma incidence and mortality. Pigment Cell Melanoma Res. 2013;26(1):9–15.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Johnson JA, Beckman MJ, Pansini-Porta A, Christakos S, Bruns ME, Beitz DC, et al. Age and gender effects on 1,25-dihydroxyvitamin D3-regulated gene expression. Exp Gerontol. 1995;30(6):631–43.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Evans SR, Houghton AM, Schumaker L, Brenner RV, Buras RR, Davoodi F, et al. Vitamin D receptor and growth inhibition by 1,25-dihydroxyvitamin D3 in human malignant melanoma cell lines. J Surg Res. 1996;61(1):127–33.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Essa S, Denzer N, Mahlknecht U, Klein R, Collnot EM, Tilgen W, et al. VDR microRNA expression and epigenetic silencing of vitamin D signaling in melanoma cells. J Steroid Biochem Mol Biol. 2010;121(1-2):110–3.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Seifert M, Rech M, Meineke V, Tilgen W, Reichrath J. Differential biological effects of 1,25-dihydroxyVitamin D3 on melanoma cell lines in vitro. J Steroid Biochem Mol Biol. 2004;89-90(1-5):375–9.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Frampton RJ, Omond SA, Eisman JA. Inhibition of human cancer cell growth by 1,25-dihydroxyvitamin D3 metabolites. Cancer Res. 1983;43(9):4443–7.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Frampton RJ, Suva LJ, Eisman JA, Findlay DM, Moore GE, Moseley JM, et al. Presence of 1,25-dihydroxyvitamin D3 receptors in established human cancer cell lines in culture. Cancer Res. 1982;42(3):1116–9.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Danielsson C, Fehsel K, Polly P, Carlberg C. Differential apoptotic response of human melanoma cells to 1 alpha,25-dihydroxyvitamin D3 and its analogues. Cell Death Differ. 1998;5(11):946–52.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Colston K, Colston MJ, Feldman D. 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology. 1981;108(3):1083–6.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Yudoh K, Matsuno H, Kimura T. 1alpha,25-dihydroxyvitamin D3 inhibits in vitro invasiveness through the extracellular matrix and in vivo pulmonary metastasis of B16 mouse melanoma. J Lab Clin Med. 1999;133(2):120–8.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Newton-Bishop JA, Beswick S, Randerson-Moor J, Chang YM, Affleck P, Elliott F, et al. Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. J Clin Oncol. 2009;27(32):5439–44.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Yang X, Schadt EE, Wang S, Wang H, Arnold AP, Ingram-Drake L, et al. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 2006;16(8):995–1004.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Gabory A, Attig L, Junien C. Sexual dimorphism in environmental epigenetic programming. Mol Cell Endocrinol. 2009;304(1-2):8–18.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Dorak MT, Karpuzoglu E. Gender differences in cancer susceptibility: an inadequately addressed issue. Front Genet. 2012;3:268.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Edgren G, Liang L, Adami HO, Chang ET. Enigmatic sex disparities in cancer incidence. Eur J Epidemiol. 2012;27(3):187–96.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Wu H, Luo J, Yu H, Rattner A, Mo A, Wang Y, et al. Cellular resolution maps of X chromosome inactivation: implications for neural development, function, and disease. Neuron. 2014;81(1):103–19.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434(7031):400–4.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Indsto JO, Nassif NT, Kefford RF, Mann GJ. Frequent loss of heterozygosity targeting the inactive X chromosome in melanoma. Clin Cancer Res. 2003;9(17):6476–82.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Elsheikh M, Dunger DB, Conway GS, Wass JA. Turner’s syndrome in adulthood. Endocr Rev. 2002;23(1):120–40.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA. Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol. 2008;9(3):239–46.CrossRefPubMedGoogle Scholar
  135. 135.
    Guo X, Su B, Zhou Z, Sha J. Rapid evolution of mammalian X-linked testis microRNAs. BMC Genomics. 2009;10:97.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Sotiropoulou G, Pampalakis G, Lianidou E, Mourelatos Z. Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell. RNA. 2009;15(8):1443–61.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Brown CJ, Hendrich BD, Rupert JL, Lafreniere RG, Xing Y, Lawrence J, et al. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell. 1992;71(3):527–42.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell. 2013;152(4):727–42.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Ruteshouser EC, Robinson SM, Huff V. Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumors. Genes Chromosomes Cancer. 2008;47(6):461–70.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science. 1997;275(5307):1790–2.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Rimm DL, Caca K, Hu G, Harrison FB, Fearon ER. Frequent nuclear/cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma. Am J Pathol. 1999;154(2):325–9.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Rivera MN, Kim WJ, Wells J, Driscoll DR, Brannigan BW, Han M, et al. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science. 2007;315(5812):642–5.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Tu Y, Wu W, Wu T, Cao Z, Wilkins R, Toh BH, et al. Antiproliferative autoantigen CDA1 transcriptionally up-regulates p21(Waf1/Cip1) by activating p53 and MEK/ERK1/2 MAPK pathways. J Biol Chem. 2007;282(16):11722–31.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Kandalaft LE, Zudaire E, Portal-Nunez S, Cuttitta F, Jakowlew SB. Differentially expressed nucleolar transforming growth factor-beta1 target (DENTT) exhibits an inhibitory role on tumorigenesis. Carcinogenesis. 2008;29(6):1282–9.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Ebert LM, Tan BS, Browning J, Svobodova S, Russell SE, Kirkpatrick N, et al. The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res. 2008;68(8):3001–9.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Tan B. FOXP3 over-expression inhibits melanoma tumorigenesis via effects on proliferation and apoptosis. Oncotarget. 2013;5(1):264–76.PubMedCentralGoogle Scholar
  147. 147.
    Tan B. Pigment Cell Melanoma Res. 2012;25(3):398–400.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Kido T, Lau YF. The human Y-encoded testis-specific protein interacts functionally with eukaryotic translation elongation factor eEF1A, a putative oncoprotein. Int J Cancer. 2008;123(7):1573–85.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Yin YH, Li YY, Qiao H, Wang HC, Yang XA, Zhang HG, et al. TSPY is a cancer testis antigen expressed in human hepatocellular carcinoma. Br J Cancer. 2005;93(4):458–63.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell. 2012;150(2):251–63.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Kido T, Ou JH, Lau YF. The X-linked tumor suppressor TSPX interacts and promotes degradation of the hepatitis B viral protein HBx via the proteasome pathway. PLoS One. 2011;6(7):e22979.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Dreumont N, Bourgeois CF, Lejeune F, Liu Y, Ehrmann IE, Elliott DJ, et al. Human RBMY regulates germline-specific splicing events by modulating the function of the serine/arginine-rich proteins 9G8 and Tra2-{beta}. J Cell Sci. 2010;123(Pt 1):40–50.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Liu Y, Bourgeois CF, Pang S, Kudla M, Dreumont N, Kister L, et al. The germ cell nuclear proteins hnRNP G-T and RBMY activate a testis-specific exon. PLoS Genet. 2009;5(11):e1000707.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Mahadevaiah SK, Odorisio T, Elliott DJ, Rattigan A, Szot M, Laval SH, et al. Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities. Hum Mol Genet. 1998;7(4):715–27.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Tsuei DJ, Hsu HC, Lee PH, Jeng YM, Pu YS, Chen CN, et al. RBMY, a male germ cell-specific RNA-binding protein, activated in human liver cancers and transforms rodent fibroblasts. Oncogene. 2004;23(34):5815–22.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Tsuei DJ, Lee PH, Peng HY, Lu HL, Su DS, Jeng YM, et al. Male germ cell-specific RNA binding protein RBMY: a new oncogene explaining male predominance in liver cancer. PLoS One. 2011;6(11):e26948.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Adi Nosrati
    • 1
    • 2
  • Maria L. Wei
    • 1
    • 2
  1. 1.Department of DermatologyUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Dermatology ServiceVeterans Affairs Medical CenterSan FranciscoUSA

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